Fetal growth restriction impairs hippocampal neurogenesis and cognition via Tet1 in offspring.

Fetal growth restriction (FGR) increases the risk for impaired cognitive function later in life. However, the precise mechanisms remain elusive. Using dexamethasone-induced FGR and protein restriction-influenced FGR mouse models, we observe learning and memory deficits in adult FGR offspring. FGR induces decreased hippocampal neurogenesis from the early post-natal period to adulthood by reducing the proliferation of neural stem cells (NSCs). We further find a persistent decrease of Tet1 expression in hippocampal NSCs of FGR mice. Mechanistically, Tet1 downregulation results in hypermethylation of the Dll3 and Notch1 promoters and inhibition of Notch signaling, leading to reduced NSC proliferation. Overexpression of Tet1 activates Notch signaling, offsets the decline in neurogenesis, and enhances learning and memory abilities in FGR offspring. Our data indicate that a long-term decrease in Tet1/Notch signaling in hippocampal NSCs contributes to impaired neurogenesis following FGR and could serve as potential targets for the intervention of FGR-related cognitive disorders.

Severe early-onset fetal growth restriction: What do we tell the prospective parents?

Fetal growth restriction (FGR) is a common complication of pregnancy, associated with higher risk of perinatal mortality and adverse health and developmental outcomes for surviving infants. True FGR relates to a pathological restriction of fetal growth resulting from complex interactions between maternal, placental, fetal, and environmental factors. Early-onset FGR (onset <32 weeks' gestation) is often first suspected at routine mid-trimester sonographic assessment of fetal morphology, or identified as part of the placental syndrome, commonly maternal pre-eclampsia. Prenatal investigations may identify the cause of FGR. Timing of delivery is guided by serial sonographic surveillance of fetal growth and well-being and maternal condition, balancing the risk of stillbirth with the benefits of advancing gestation. This is particularly pertinent to severe early-onset FGR, a leading iatrogenic cause of very preterm birth. Prognosis is largely determined by the severity of FGR and its causes, gestation at birth, and birthweight. Pregnancy termination may be considered. Antenatal care and delivery in a tertiary center, provided by a multi-disciplinary team with expertise in managing high-risk pregnancies, are imperative to optimizing outcomes.

Association of Intrauterine Growth Restriction and Small for Gestational Age Status With Childhood Cognitive Outcomes: A Systematic Review and Meta-analysis.

Importance: The magnitude of the association of intrauterine growth restriction (IUGR) and small for gestational age (SGA) status with cognitive outcomes in preterm and term-born children has not been established. Objective: To examine cognitive outcomes of preterm and term-born children who had IUGR and were SGA compared with children who were appropriate for gestational age (AGA) during the first 12 years of life. Data Sources: For this systematic review and meta-analysis, the Scopus, PubMed, Web of Science, Science Direct, PsycInfo, and ERIC databases were searched for English-language, peer-reviewed literature published between January 1, 2000, and February 20, 2020. The following Medical Subject Heading terms for IUGR and SGA and cognitive outcomes were used: intrauterine growth restriction, intrauterine growth retardation, small for gestational age AND neurodevelopment, neurodevelopmental outcome, developmental outcomes, and cognitive development. Study Selection: Inclusion criteria were assessment of cognitive outcomes (full-scale IQ or a cognitive subscale), inclusion of an AGA group as comparison group, and inclusion of gestational age at birth and completion of cognitive assessment up to 12 years of age. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines were followed. Data were double screened for full-text articles, and a subset were independently coded by 2 authors. Standardized mean differences (SMDs) and odd ratios from individual studies were pooled by applying random-effects models. Main Outcomes and Measures: Cognitive outcomes, defined as mental, cognitive, or IQ scores, estimated with standardized practitioner-based cognitive tests or as borderline intellectual impairment (BII), defined as mental, cognitive, or IQ scores at least 1 SD below the mean cognitive score. Results: In this study of 89 samples from 60 studies including 52 822 children, children who had IUGR and were SGA had significantly poorer cognitive outcomes (eg, cognitive scores and BII) than children with AGA in childhood. For cognitive scores, associations are consistent for preterm (SMD, -0.27; 95% CI, -0.38 to -0.17) and term-born children (SMD, -0.39; 95% CI, -0.50 to -0.28), with higher effect sizes reported for term-born IUGR and AGA group comparisons (SMD, -0.58; 95% CI, -0.82 to -0.35). Analyses on BII revealed a significantly increased risk in the preterm children who had IUGR and were SGA (odds ratio, 1.57; 95% CI, 1.40-1.77) compared with the children with AGA. Conclusions and Relevance: Growth vulnerabilities assessed antenatally (IUGR) and at the time of birth (SGA) are significantly associated with lower childhood cognitive outcomes in preterm and term-born children compared with children with AGA. These findings highlight the need to develop interventions that boost cognitive functions in these high-risk groups.

Postnatal delayed growth impacts cognition but rescues programmed impaired pulmonary vascular development in an IUGR rat model.

BACKGROUND AND AIMS: Intrauterine growth restriction (IUGR) is a state of slower fetal growth usually followed by a catch-up growth. Postnatal catch-up growth in IUGR models increases the incidence of pulmonary arterial hypertension in adulthood. Here, we hypothesize that the adverse pulmonary vascular consequences of IUGR may be improved by slowing down postnatal growth velocity. Meanwhile, cognitive function was also studied. METHODS AND RESULTS: We established an IUGR rat model by restricting maternal food throughout gestation. After birth, pups were fed a regular or restricted diet during lactation by changing litter size. Thus, there were three experimental groups according to the dam/offspring diet: C/C (gold standard), IUGR with catch-up growth (R/C) and IUGR with delayed growth (R/D). In adulthood (14 weeks of age), we assessed pulmonary vascular development by hemodynamic measurement and immunohistochemistry. Our results showed that adult R/C offspring developed an elevated mean pulmonary arterial pressure (mPAP) and pulmonary arteriolar remodeling accompanied with decreased eNOS mRNA and protein expressions compared to C/C or R/D offspring. This suggested that delayed postnatal growth improved pulmonary circulation compared to postnatal catch-up growth. Conversely, adult R/D offspring performed poorly in cognition. Behavior test and electrophysiology results exhibited a reduced synaptic plasticity. Furthermore, decreased mRNA expression levels of the memory-related gene zif268 and transcription factor recruitment factor p300 in the hippocampus region were also observed in R/D group. CONCLUSION: These findings indicate that delayed postnatal growth results in cognitive impairment, but it reverses elevations in mPAP induced by postnatal catch-up growth following IUGR.

Women's lived experiences of a prenatal diagnosis of fetal growth restriction at the limits of viability: An interpretative phenomenological study.

OBJECTIVES: The research team aimed to understand women's lived experiences during pregnancies with poor prognosis following prenatal detection of Fetal Growth Restriction at the limits of viability (FGRLV). METHODS: Qualitative interviews with six women who had attended a specialist service following a prenatal diagnosis of FGRLV were conducted. The interview data were analysed using interpretative phenomenological analysis. FINDINGS: Three superordinate themes alongside thirteen subthemes were identified. Theme 1 described 'a fine line between supportive and unhelpful' care experiences. A second theme of 'understanding the situation and decisions to be made' described how women faced many uncertainties. The final theme of 'parental responsibility' reflected how women imagined their futures to have been, exploring their embodied parental role and connection to their unborn or young child. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Women highlighted the importance of maternal healthcare teams providing clear information and reassurance to them. They also reported that prior experiences were important to them in influencing their perception of that pregnancy. Furthermore, women reflected on their desperation for a positive outcome. Understanding these factors can enable maternal healthcare teams to facilitate informed decision-making and provide individualised emotional support for women. Our findings will enable maternal care teams to better support women in similar clinical situations.

Exposure to Community Homicide During Pregnancy and Adverse Birth Outcomes: A Within-Community Matched Design.

BACKGROUND: Community violence is an understudied aspect of social context that may affect risk of preterm birth and small-for-gestational age (SGA). METHODS: We matched California mothers with live singleton births who were exposed to a homicide in their Census tract of residence in 2007-2011 to unexposed mothers within the same tract. We estimated risk differences with a weighted linear probability model, with weights corresponding to the matched data structure. We estimated the average treatment effect on the treated of homicide exposure on the risk of preterm birth and SGA during the preconception period and first and second trimester. RESULTS: We found a small increase in risk of SGA associated with homicide exposure in the first trimester (0.14% [95% confidence interval (CI) = -0.01%, 0.30%]), but not for exposure during the preconception period (-0.01% [95% CI = -0.17%, 0.15%]) or the second trimester (-0.06% [95% CI = -0.23%, 0.11%]). Risk of preterm birth was not affected by homicide exposure. When women were exposed to homicides during all three exposure windows, there was a larger increase in risk of SGA (1.09% [95% CI = 0.15%, 2.03%]) but not preterm birth (0.14% [95% CI = -0.74%, 1.01%]). Exposure to three or more homicides was also associated with greater risk of SGA (0.78% [95% CI = 0.15%, 1.40%]). Negative controls indicated that residual confounding by temporal patterning was unlikely. CONCLUSIONS: Homicide exposure during early pregnancy is associated with a small increased risk of SGA.

Pregnant women's experiences and perceptions of participating in the EVERREST prospective study; a qualitative study.

BACKGROUND: The EVERREST Prospective Study is a multicentre observational cohort study of pregnancies affected by severe early-onset fetal growth restriction. The study recruits women with singleton pregnancies where the estimated fetal weight is less than the 3rd centile and below 600 g, between 20 + 0 and 26 + 6 weeks of pregnancy, in the absence of a known chromosomal, structural or infective cause. METHOD: The reported study was retrospective descriptive qualitative interview study of women who had participated in the EVERREST Prospective Study. The aim of this study was to explore the experiences and perceptions of pregnant women taking part in research during a pregnancy affected by severe early-onset fetal growth restriction. Audio-recorded semi-structured telephone interviews were conducted with a purposive sample of 12 women, at least 1 year after delivery of their baby. Two of these pregnancies had ended in stillbirth and one in neonatal death, reflecting the outcomes seen in the EVERREST Prospective Study. Participants gave informed consent, were 16 years or older and were interviewed in English. A topic guide was used to ensure a consistent approach. Questions focused on pregnancy experiences, involvement with the EVERREST study and potential involvement in future research. Recordings were transcribed verbatim for thematic analysis using NVivo10. RESULTS: Four broad themes were identified; 'before joining the EVERREST Prospective Study', 'participating in research', 'information and support' and 'looking back and looking forwards'. Each broad theme incorporated several subthemes. All participants recalled their reaction to being told their baby was smaller than expected. The way this news was given had a lasting impact. A range of benefits of participation in the EVERREST Prospective Study were described and the participants were positive about the way it was conducted. As a consequence, they were receptive to participating in future research. However, the findings suggest that research teams should be sensitive when approaching families at a difficult time or when they are already participating in other research. CONCLUSIONS: This study highlights the willingness of pregnant women to participate in research and identifies strategies for researchers to engage participants.

Early psychosocial development of small for gestational age and intrauterine growth-restricted children: a systematic review.

OBJECTIVE: To examine evidence regarding psychosocial development from one month to four years of age in small for gestational age and intrauterine growth-restricted children. STUDY DESIGN: Studies were included if participants met criteria for small for gestational age or intrauterine growth restriction, follow-up was from age 1 month to 4 years, methods were described, and appropriate comparison groups were included. Methodological quality of included studies was assessed using quality-appraisal guidelines. RESULTS: Of 3216 studies reviewed, 24 were included. Poorer psychosocial development was described for small for gestational age children in 15 and for intrauterine growth-restricted children in 3 studies. Only 5 studies measured placental insufficiency using Doppler ultrasound. Study heterogeneity limited synthesis and interpretation. CONCLUSIONS: Although evidence suggests that small for gestational age children are at risk of poorer early childhood psychosocial outcomes, further research is required to clarify whether placental insufficiency is associated with poorer early psychosocial development.

Depression in pregnant women hospitalized due to intrauterine growth restriction: Prevalence and associated factors.

OBJECTIVE: Pregnancies complicated with intrauterine growth restriction (IUGR) may require hospitalization in a high-risk pregnancy unit (HRPU). A complicated pregnancy and hospital admission may negatively affect the pregnant woman's mental health. Several factors have been identified as possible risk factors for depression, which is proven to lead to several adverse perinatal outcomes. The purpose of this study was to screen for depression in women admitted to an HRPU due to IUGR pregnancy and also to identify associated risk factors. STUDY DESIGN: All pregnant women admitted at ≥ 24 gestational weeks with the diagnosis of IUGR were eligible for the study. The Greek version of the Edinburgh Postnatal Depression Scale was used as screening tool on admission. A cut-off score ≥ 13 was used to identify depression, while possible risk factors were also investigated. RESULTS: Overall, 73 women were eligible for the study and agreed to complete the questionnaire. The mean age of the pregnant women was 31.4 ±â€¯6.7 years and the mean gestational week at admission was 33.6 ±â€¯2.9 weeks. The prevalence of depressive symptoms (score ≥ 13) was 32.9% (24/73). In the multivariable model, depressive symptoms were significantly correlated with lower gestational age (OR: 3.459 95%CI: 1.124-10.648) and smoking during pregnancy (OR: 3.926 95% CI: 1.141-13.507). CONCLUSIONS: About one third of pregnant women hospitalized in the HRPU with IUGR pregnancies showed signs of depression at the time of admission. Early-IUGR and smoking were found to be associated with antenatal depressive symptoms.

Obstetric Phenotypes in the Heterogeneity of Schizophrenia.

Schizophrenia is a complex mental disorder with genetic and environmental components. Obstetric complications (OCs) are one of the most common environmental risk factors described. However, despite being different in timing and outcome, OCs are usually described as a homogeneous entity. In the present study, we evaluate the presence of different patterns of OCs evaluated with the Lewis-Murray Scale in chronic schizophrenia patients (n = 101) and their association with a crude marker of the intrauterine environment such as weight at birth.OCs related with abnormal fetal growth (p < 0.001) and OCs during gestation (p = 0.003) were associated with lower birth weight. However, difficulties in delivery, complications in pregnancy, and OCs all together (as a set) were not associated with weight at birth.Our results infer that OCs cannot be taken as a homogeneous group. Different patterns of OCs result in different birth weights, which is associated with specific metabolic, cognitive, and brain structure outcomes.

Neurodevelopment at Age 10 Years of Children Born <28 Weeks With Fetal Growth Restriction.

OBJECTIVES: We sought to evaluate the relationships between fetal growth restriction (FGR) (both severe and less severe) and assessments of cognitive, academic, and adaptive behavior brain function at age 10 years. METHODS: At age 10 years, the Extremely Low Gestational Age Newborns Cohort Study assessed the cognitive function, academic achievement, social-communicative function, psychiatric symptoms, and overall quality of life of 889 children born before 28 weeks' gestation. A pediatric epileptologist also interviewed parents as part of a seizure evaluation. The 52 children whose birth weight z scores were <-2 were classified as having severe FGR, and the 113 whose birth weight z scores were between -2 and -1 were considered to have less severe FGR. RESULTS: The more severe the growth restriction in utero, the lower the level of function on multiple cognitive and academic achievement assessments performed at age 10 years. Growth-restricted children were also more likely than their extremely preterm peers to have social awareness impairments, autistic mannerisms, autism spectrum diagnoses, difficulty with semantics and speech coherence, and diminished social and psychosocial functioning. They also more frequently had phobias, obsessions, and compulsions (according to teacher, but not parent, report). CONCLUSIONS: Among children born extremely preterm, those with severe FGR appear to be at increased risk of multiple cognitive and behavioral dysfunctions at age 10 years, raising the possibility that whatever adversely affected their intrauterine growth also adversely affected multiple domains of cognitive and neurobehavioral development.

Maternal depression and anxiety and fetal-neonatal growth / Depressão e ansiedade maternal e crescimento fetal-neonatal

Abstract Objective: Maternal depression and anxiety have been found to negatively affect fetal and neonatal growth. However, the independent effects of maternal depression and anxiety on fetal-neonatal growth outcomes and trajectories remain unclear. This study aimed to analyze simultaneously the effects of maternal prenatal depression and anxiety on (1) neonatal growth outcomes, and (2), on fetal-neonatal growth trajectories, from the 2nd trimester of pregnancy to childbirth. Methods: A sample of 172 women was recruited and completed self-reported measures of depression and anxiety during the 2nd and 3rd trimesters of pregnancy, and at childbirth. Fetal and neonatal biometrical data were collected from clinical reports at the same assessment moments. Results: Neonates of prenatally anxious mothers showed lower weight (p = 0.006), length (p = 0.025), and ponderal index (p = 0.049) at birth than neonates of prenatally non-anxious mothers. Moreover, fetuses-neonates of high-anxiety mothers showed a lower increase of weight from the 2nd trimester of pregnancy to childbirth than fetuses-neonates of low-anxiety mothers (p < 0.001). Considering maternal depression and anxiety simultaneously, only the effect of maternal anxiety was found on these markers of fetal-neonatal growth outcomes and trajectories. Conclusion: This study demonstrates the independent longitudinal effect of maternal anxiety on major markers of fetal-neonatal growth outcomes and trajectories, simultaneously considering the effect of maternal depression and anxiety.

Resumo Objetivo: Foi constatado que a depressão e ansiedade materna afetam negativamente o crescimento fetal e neonatal. Contudo, o efeito independente da depressão e ansiedade materna sobre os resultados e as trajetórias de crescimento fetal e neonatal continua incerto. Este estudo visou a analisar simultaneamente o efeito da depressão e ansiedade materna pré-natal (1) sobre os resultados de crescimento neonatal e (2) sobre as trajetórias do crescimento fetal-neonatal a partir do 2° trimestre de gravidez até o parto. Métodos: Uma amostra de 172 mulheres foi recrutada e elas relataram graus de depressão e ansiedade no 2° e 3° trimestre de gravidez e parto. Os dados biométricos fetais e neonatais foram coletados dos prontuários clínicos nas mesmas ondas de avaliação. Resultados: Os neonatos de mães ansiosas no período pré-natal mostraram menor peso (p = 0,006), comprimento (p = 0,025) e índice ponderal (p = 0,049) no nascimento do que os neonatos de mães não ansiosas no período pré-natal. Além disso, os neonatos de mães muito ansiosas mostraram um menor aumento de peso do 2° trimestre de gravidez até o parto que os fetos-neonatos de mães pouco ansiosas (p < 0,001). Considerando simultaneamente a depressão e a ansiedade maternal, apenas o efeito da ansiedade materna foi constatado nesses marcadores de resultados e trajetórias de crescimento fetal-neonatal. Conclusão: Este estudo demonstra o efeito longitudinal independente da ansiedade materna sobre os principais marcadores de resultados e trajetórias de crescimento fetal-neonatal, considerando simultaneamente o efeito da depressão e ansiedade materna.

The extent of intrauterine growth restriction determines the severity of cerebral injury and neurobehavioural deficits in rodents.

BACKGROUND: Cerebral Palsy (CP) is the most common physical pediatric neurodevelopmental disorder and spastic diplegic injury is its most frequent subtype. CP results in substantial neuromotor and cognitive impairments that have significant socioeconomic impact. Despite this, its underlying pathophysiological mechanisms and etiology remain incompletely understood. Furthermore, there is a need for clinically relevant injury models, which a) reflect the heterogeneity of the condition and b) can be used to evaluate new translational therapies. To address these key knowledge gaps, we characterized a chronic placental insufficiency (PI) model, using bilateral uterine artery ligation (BUAL) of dams. This injury model results in intrauterine growth restriction (IUGR) in pups, and animals recapitulate the human phenotype both in terms of neurobehavioural and anatomical deficits. METHODS: Effects of BUAL were studied using luxol fast blue (LFB)/hematoxylin & eosin (H&E) staining, immunohistochemistry, quantitative Magnetic Resonance Imaging (MRI), and Catwalk neurobehavioural tests. RESULTS: Neuroanatomical analysis revealed regional ventricular enlargement and corpus callosum thinning in IUGR animals, which was correlated with the extent of growth restriction. Olig2 staining revealed reductions in oligodendrocyte density in white and grey matter structures, including the corpus callosum, optic chiasm, and nucleus accumbens. The caudate nucleus, along with other brain structures such as the optic chiasm, internal capsule, septofimbrial and lateral septal nuclei, exhibited reduced size in animals with IUGR. The size of the pretectal nucleus was reduced only in moderately injured animals. MAG/NF200 staining demonstrated reduced myelination and axonal counts in the corpus callosum of IUGR animals. NeuN staining revealed changes in neuronal density in the hippocampus and in the thickness of hippocampal CA2 and CA3 regions. Diffusion weighted imaging (DWI) revealed regional white and grey matter changes at 3 weeks of age. Furthermore, neurobehavioural testing demonstrated neuromotor impairments in animals with IUGR in paw intensities, swing speed, relative print positions, and phase dispersions. CONCLUSIONS: We have characterized a rodent model of IUGR and have demonstrated that the neuroanatomical and neurobehavioural deficits mirror the severity of the IUGR injury. This model has the potential to be applied to examine the pathobiology of and potential therapeutic strategies for IUGR-related brain injury. Thus, this work has potential translational relevance for the study of CP.

A Program Aimed at Reducing Anxiety in Pregnant Women Diagnosed With a Small-for-Gestational-Age Fetus: Evaluative Findings From a Spanish Study.

The objective of this study was to evaluate the effect of anxiety-reducing techniques including music therapy, sophrology, and creative visualization in pregnant women with a fetus diagnosed as small for gestational age and improved fetal and neonatal weight. This was a quasi-experimental study with a nonrandomized clinical trial design. We compared 2 groups of pregnant women with a fetus diagnosed as small for gestational age with no abnormalities on Doppler studies. The control group (n = 93) received standard care, and the intervention group (n = 65), in addition to standard care, underwent a program of 6 sessions led by a midwife or nurse who taught anxiety-reduction techniques. The State-Trait Anxiety Inventory (STAI) including trait and state subscales were completed by both groups at the start of the study, and only the STAI-State subscale was completed again at the end of the study. Comparisons between the 2 groups regarding fetal weight and centile and maternal STAI scores were performed using the t test and the χ test. There were no significant differences in the STAI-Trait scores between the 2 groups. There were statistically significant differences in the intervention group's STAI-State score percentiles between the start and the end of the study, being lower at the end of the study (P < .001). There were significant differences between the 2 groups in fetal weight trajectory on the basis of fetal weight: the intervention group had a larger weight gain (P < .005). The program designed to reduce anxiety in pregnant women was effective at reducing anxiety in the women in the intervention group, leading to a favorable fetal weight trajectory in this group.

Influence of catch up growth on spatial learning and memory in a mouse model of intrauterine growth restriction.

BACKGROUND: Intrauterine growth restriction (IUGR) and rapid postnatal weight gain or catch up growth (CUG) increase the susceptibility to metabolic syndrome during adult life. Longitudinal studies have also revealed a high incidence of learning difficulties in children with IUGR. The aim of the present study was to investigate the effect of nutrition and CUG on learning memory in an IUGR animal model. We hypothesized that synaptic protein expression and transcription, an essential mechanism for memory consolidation, might be affected by intrauterine undernutrition. METHODS: IUGR was induced by 50% maternal caloric undernutrition throughout late gestation. During the suckling period, dams were either fed ad libitum or food restricted. The pups were divided into: Normal prenatal diet-Normal postnatal diet (NN), Restricted prenatal diet- Normal postnatal diet + catch up growth (RN+), Normal prenatal diet-Restricted postnatal diet (NR) and Restricted prenatal diet-Restricted postnatal diet (RR). At 4 weeks of age, memory was assessed via a water maze test. To evaluate synaptic function, 2 specific synaptic proteins (postsynaptic density-95 [PSD95], synaptophysin) as well as insulin receptors (IR) were tested by Western Blot and quantitative polymerase chain reaction (qPCR). Brain-derived neurotrophic factor and serum insulin levels were also studied. RESULTS AND CONCLUSIONS: The RN+ group presented a learning curve similar to the NN animals. The RR animals without CUG showed learning disabilities. PSD95 was lower in the RR group than in the NN and RN+ mice. In contrast, synaptophysin was similar in all groups. IR showed an inverse expression pattern to that of the PSD95. In conclusion, perinatal nutrition plays an important role in learning. CUG after a period of prenatal malnutrition seems to improve learning skills. The functional alterations observed might be related to lower PSD95 activity and a possible dysfunction in the hormone regulation of synaptic plasticity.

Maternal depression and anxiety and fetal-neonatal growth.

OBJECTIVE: Maternal depression and anxiety have been found to negatively affect fetal and neonatal growth. However, the independent effects of maternal depression and anxiety on fetal-neonatal growth outcomes and trajectories remain unclear. This study aimed to analyze simultaneously the effects of maternal prenatal depression and anxiety on (1) neonatal growth outcomes, and (2), on fetal-neonatal growth trajectories, from the 2nd trimester of pregnancy to childbirth. METHODS: A sample of 172 women was recruited and completed self-reported measures of depression and anxiety during the 2nd and 3rd trimesters of pregnancy, and at childbirth. Fetal and neonatal biometrical data were collected from clinical reports at the same assessment moments. RESULTS: Neonates of prenatally anxious mothers showed lower weight (p=0.006), length (p=0.025), and ponderal index (p=0.049) at birth than neonates of prenatally non-anxious mothers. Moreover, fetuses-neonates of high-anxiety mothers showed a lower increase of weight from the 2nd trimester of pregnancy to childbirth than fetuses-neonates of low-anxiety mothers (p<0.001). Considering maternal depression and anxiety simultaneously, only the effect of maternal anxiety was found on these markers of fetal-neonatal growth outcomes and trajectories. CONCLUSION: This study demonstrates the independent longitudinal effect of maternal anxiety on major markers of fetal-neonatal growth outcomes and trajectories, simultaneously considering the effect of maternal depression and anxiety.

Brain metabolite alterations in infants born preterm with intrauterine growth restriction: association with structural changes and neurodevelopmental outcome.

BACKGROUND: Intrauterine growth restriction and premature birth represent 2 independent problems that may occur simultaneously and contribute to impaired neurodevelopment. OBJECTIVE: The objective of the study was to assess changes in the frontal lobe metabolic profiles of 1 year old intrauterine growth restriction infants born prematurely and adequate-for-gestational-age controls, both premature and term adequate for gestational age and their association with brain structural and biophysical parameters and neurodevelopmental outcome at 2 years. STUDY DESIGN: A total of 26 prematurely born intrauterine growth restriction infants (birthweight <10th centile for gestational age), 22 prematurely born but adequate for gestational age controls, and 26 term adequate-for-gestational-age infants underwent brain magnetic resonance imaging and magnetic resonance spectroscopy at 1 year of age during natural sleep, on a 3 Tesla scanner. All brain T1-weighted and diffusion-weighted images were acquired along with short echo time single-voxel proton spectra from the frontal lobe. Magnetic resonance imaging/magnetic resonance spectroscopy data were processed to derive structural, biophysical, and metabolic information, respectively. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales 3rd edition, assessing cognitive, language, motor, socioemotional, and adaptive behavior. RESULTS: Prematurely born intrauterine growth restriction infants had slightly smaller brain volumes and increased frontal lobe white matter mean diffusivity compared with both prematurely born but adequate for gestational age and term adequate for gestational age controls. Frontal lobe N-acetylaspartate levels were significantly lower in prematurely born intrauterine growth restriction than in prematurely born but adequate for gestational age infants but increased in prematurely born but adequate for gestational age compared with term adequate-for-gestational-age infants. The prematurely born intrauterine growth restriction group also showed slightly lower choline compounds, borderline decrements of estimated glutathione levels, and increased myoinositol to choline ratios, compared with prematurely born but adequate for gestational age controls. These specific metabolite changes were locally correlated to lower gray matter content and increased mean diffusivity and reduced white matter fraction and fractional anisotropy. Prematurely born intrauterine growth restriction infants also showed a tendency for poorer neurodevelopmental outcome at 2 years, associated with lower levels of frontal lobe N-acetylaspartate at 1 year within the preterm subset. CONCLUSIONS: Preterm intrauterine growth restriction infants showed altered brain metabolite profiles during a critical stage of brain maturation, which correlate with brain structural and biophysical parameters and neurodevelopmental outcome. Our results suggest altered neurodevelopmental trajectories in preterm intrauterine growth restriction and adequate-for-gestational-age infants, compared with term adequate-for-gestational-age infants, which require further characterization.

Aspirin adherence during high-risk pregnancies, a questionnaire study.

OBJECTIVE: Aspirin reduces the risk of recurrent hypertensive disorders of pregnancy (HD) and fetal growth restriction (FGR). This study examined the non-adherence rates of aspirin in women with high-risk pregnancies. STUDY DESIGN: All consecutive women between 24 and 36weeks gestation with an indication for aspirin use during pregnancy were invited for this study. A survey was used which included two validated questionnaires, the simplified medication adherence questionnaire (SMAQ) and the Beliefs and Behaviour Questionnaire (BBQ). MAIN OUTCOME MEASURES: To determine the non-adherence rates of aspirin, and to identify the beliefs and behavior concerning aspirin. RESULTS: Indications for aspirin use during pregnancy were previous HD, FGR, intrauterine fetal death or current maternal disease. Non-adherence rates according to the SMAQ and BBQ were 46.3% and 21.4% respectively. No differences in demographic background or obstetrical characteristics between adherent and non-adherent women could be demonstrated. CONCLUSIONS: Adherence for aspirin in this high-risk population cannot be taken for granted. The non-adherence rates in pregnant women are comparable with the non-adherence rates for aspirin in the non-pregnant population.

Programming the brain: Common outcomes and gaps in knowledge from animal studies of IUGR.

IUGR in humans is associated with impaired pre- and postnatal neurodevelopment, and subsequent postnatal cognition, resulting in lower IQ, poorer memory, visuomotor and executive function skills, as well as behavioural and attentional problems. Experimental models of IUGR are needed to allow direct testing of causality and interventions, and have benefits in reducing both confounding by comorbidities such as prematurity, and variation due to environment and genetics. This review describes and discusses experimental models of IUGR in which neurodevelopmental and cognitive outcomes of IUGR have been reported. We consider the timing of neurodevelopment relative to birth and to the period of restriction, as well as the effects of each experimental perturbation on the fetal environment and development, before discussing neurodevelopmental and cognitive outcomes for progeny as fetuses, neonates and into adolescent and adult life. Experimental IUGR induces broadly similar outcomes to human IUGR, with altered brain morphology, in particular grey matter loss and discordant trajectory of white matter development, and poorer cognition and memory reported in various studies. Nevertheless, there remain gaps in knowledge of neurodevelopment in experimental models. We end the review with recommendations for the design of future studies to further investigate the mechanisms underlying adverse neurodevelopmental consequences of IUGR, and to evaluate interventions that may subsequently improve outcomes of IUGR in humans.

Cognitive and Behavioral Outcomes of Intrauterine Growth Restriction School-Age Children.

CONTEXT: Children who experienced intrauterine growth restriction (IUGR) may be at increased risk for adverse neurologic developmental outcomes during the school-age years of life. OBJECTIVE: To estimate the effect of IUGR on cognition and behavior in school-aged children. DATA SOURCES: Medline, Embase, and PsycINFO were searched for English-language articles published after 1980. DATA SELECTION: We included case-control studies reporting cognitive and/or behavioral data of children who had IUGR and were evaluated afterfifth birthday. DATA EXTRACTION: Cognitive data from 15 studies and behavioral data from 6 studies were selected with a total of 1559 cases and 1630 controls. The cognitive scores and behavioral outcomes were extracted. RESULTS: The controls had significantly higher cognitive scores than the children with IUGR (standardized mean difference [SMD] -0.38, 95% confidence interval [CI] -0.51 to -0.25, P < .00001). The IQ scores of the IUGR group were not significantly correlated with mean birth weight and gestational age (P > .05). Five trials were included in the behavioral outcomes trial, the behavior scores were significantly different between the groups with and without IUGR (SMD 0.31, 95% CI 0.13 to 0.48, P = .001). The incidence of attention-deficit/hyperactivity disorder (ADHD) was not significantly different between 2 groups (P = .11). LIMITATIONS: The number of studies that assessed behavioral and ADHD outcome is small. CONCLUSIONS: The findings demonstrate that IUGR is associated with lower cognitive scores in school-age children. However, further large-scale trials are needed to assess the effects of IUGR on the outcome of behavioral disorder and ADHD.